Prostate cancer (PCA) is the most frequently diagnosed malignancy in elderly men, and is rated as second leading cause of cancer deaths in men. The malignancy has long latent period of development from pre-neoplastic lesion to full-blown cancer providing ample time to intervene or alter the progression of this disease employing chemopreventive strategies. Additionally, numerous studies have shown that the risk for certain cancers could be lowered by dietary manipulations, especially by increased consumption of fruits and vegetables. Accordingly, there has been serious interest in identifying diets or dietary constituents (both nutritive and non-nutritive phytochemicals) for their potential use as chemopreventive agents. Grape seed extract (GSE), a rich and commercially available source of proanthocyanidins (also known as procyanidins), is usually consumed as a health supplement for its wide range of beneficial effects. Regarding cancer, several studies by us and others have demonstrated the anti-cancer and chemopreventive efficacy of GSE against various epithelial malignancies including PCA cells. Since GSE represents a complex mixture of polyphenols, the central focus of the studies during the last funding period was to isolate and characterize active component(s) in GSE to carry out detailed mechanistic and efficacy studies for anticancer activity employing pure and defined agents. We recently isolated and characterized procyanidin B2- 3,3'-di-O-gallate (B2-G2) as an active compound from GSE with strong anti-cancer activity against human prostate carcinoma DU145 cells. Further studies with this compound revealed that it is taken up by PCA cells and that it causes both cytotoxic as well as cell growth inhibitory effects. Additional studies revealed that B2-G2 causes both cell cycle arrest and apoptosis induction in human PCA cells carrying functional androgen receptor;these cells specifically represent majority of human prostate tumors. Importantly, B2-G2 did not show cytotoxicity in normal human prostate epithelial and stromal cells, showing its selectivity in human PCA cells. Since uncontrolled proliferation due to deregulated cell cycle progression and loss of apoptotic function are the major underlying defects in most of the cancers including PCA and since B2-G2 exerts strong cell cycle arrest and apoptotic responses in PCA cells, our central hypothesis is that procyanidin B2-3,3'-di-O-gallate selectively induces cell cycle arrest and apoptosis in neoplastic prostate epithelial cells which collectively leads to its preventive and therapeutic efficacy against PCA.
Our specific aims are to: 1) prepare B2-G2 needed for planned mechanistic, bioavailability and efficacy studies, 2) conduct in vitro studies to address mechanism of action of B2-G2 involved in cell cycle arrest and apoptosis, and 3) determine efficacy and bioavailability of B2-G2 employing an in vivo transgenic carcinoma of the mouse prostate (TRAMP) model, which closely and naturally mimics the progression of prostatic carcinoma in humans. Overall, our long term goal is to develop procyanidin B2-3,3'-di- O-gallate as a mechanism-based potential chemopreventive agent against PCA. 7. PROJECT NARRATIVE Prostate cancer is second leading cause of cancer-related deaths in United States, and thus is an important public health issue. Use of chemopreventive agents seems to be more effective approach for the control of prostate cancer as it has long latent period of development;sometimes over decade from precursor lesions to full blown disease. Current grant proposal focuses on the development of one such agent, which has been isolated from grape seed extract, a widely consumed health supplement. Outcomes of our proposed research will provide a mechanism-based agent for the prevention of prostate cancer in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA091883-10
Application #
8309786
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Parnes, Howard L
Project Start
2001-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$322,493
Indirect Cost
$111,713
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Tyagi, Alpna; Raina, Komal; Shrestha, Suraj Prakash et al. (2014) Procyanidin B2 3,3(ýýý)-di-O-gallate, a biologically active constituent of grape seed extract, induces apoptosis in human prostate cancer cells via targeting NF-*B, Stat3, and AP1 transcription factors. Nutr Cancer 66:736-46
Ting, Harold; Deep, Gagan; Agarwal, Chapla et al. (2014) The strategies to control prostate cancer by chemoprevention approaches. Mutat Res 760:1-15
Tyagi, Alpna; Raina, Komal; Gangar, Subhash et al. (2013) Differential effect of grape seed extract against human non-small-cell lung cancer cells: the role of reactive oxygen species and apoptosis induction. Nutr Cancer 65 Suppl 1:44-53
Raina, Komal; Tyagi, Alpna; Kumar, Dileep et al. (2013) Role of oxidative stress in cytotoxicity of grape seed extract in human bladder cancer cells. Food Chem Toxicol 61:187-95
Shrotriya, Sangeeta; Deep, Gagan; Gu, Mallikarjuna et al. (2012) Generation of reactive oxygen species by grape seed extract causes irreparable DNA damage leading to G2/M arrest and apoptosis selectively in head and neck squamous cell carcinoma cells. Carcinogenesis 33:848-58
Shrestha, Suraj P; Thompson, John A; Wempe, Michael F et al. (2012) Glucuronidation and methylation of procyanidin dimers b2 and 3,3?-di-o-galloyl-b2 and corresponding monomers epicatechin and 3-o-galloyl-epicatechin in mouse liver. Pharm Res 29:856-65
Chou, Shen-Chieh; Kaur, Manjinder; Thompson, John A et al. (2010) Influence of gallate esterification on the activity of procyanidin B2 in androgen-dependent human prostate carcinoma LNCaP cells. Pharm Res 27:619-27
Kaur, Manjinder; Velmurugan, Balaiya; Rajamanickam, Subapriya et al. (2009) Gallic acid, an active constituent of grape seed extract, exhibits anti-proliferative, pro-apoptotic and anti-tumorigenic effects against prostate carcinoma xenograft growth in nude mice. Pharm Res 26:2133-40
Kaur, Manjinder; Agarwal, Chapla; Agarwal, Rajesh (2009) Anticancer and cancer chemopreventive potential of grape seed extract and other grape-based products. J Nutr 139:1806S-12S
Raina, Komal; Rajamanickam, Subapriya; Deep, Gagan et al. (2008) Chemopreventive effects of oral gallic acid feeding on tumor growth and progression in TRAMP mice. Mol Cancer Ther 7:1258-67

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